tbuckley/cabot-search huggingface dataset:
DIPG-61. Preclinical efficacy of combined radiotherapy with venetoclax treatment in targeting diffuse midline gliomas
Authors: Krishna Madhavan, Ilango Balakrishnan, Senthilnath Lakshmanachetty, Angela Pierce, Bridget Sanford, Susan Fosmire, Hanan Elajaili, Faye Walker, Dong Wang, Eva Nozik-Grayck, Siddhartha Mitra, Nathan Dahl, Rajeev Vibhakar, Sujatha Venkataraman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: H3K27M diffuse midline gliomas (DMGs) are highly aggressive pediatric tumors of pons, thalamus or spinal cord. The only standard-of-care for DMGs is radiation therapy (RT) since the anatomical location of such tumors does not allow surgical resection. Tumor response to RT is at best transient as tumor becomes refractory due to radioresistance. Tumor relapse after RT is a major hurdle in treating DMGs. The mechanism of development of radioresistance due to RT-induced stress has not been studied in DMGs yet. METHODS: We performed an integrated genomic analysis to determine genes responsible for radioresistance and a targeted drug screen to identify drugs synergizing with radiation in DMG. Effect of venetoclax on radiation-naïve and 6Gy radiated DMG cells was evaluated by studying cell death and apoptosis. The efficacy of combining venetoclax with radiation was evaluated in vivo using orthotopic xenograft models. RESULTS: We identified that BCL2 as a key regulator of tumor growth in DMGs after radiation. Radiation sensitizes DMGs to venetoclax treatment. While venetoclax as a monotherapy was not cytotoxic to DMG cells, post-radiation venetoclax significantly increased cell death and apoptosis. Combining venetoclax with RT significantly enhanced the survival of mice with DMG tumors in vivo. Further, we found that the mechanism of radiation-induced cytotoxic effect of venetoclax is p53-independent in DMGs. CONCLUSIONS: This study shows that venetoclax impedes the anti-apoptotic function of radiation-induced BCL2 in DMG leading to apoptosis. Our results are encouraging because, in clinical settings, majority of the DMG patients, irrespective of the tumor p53 status, will benefit from combining RT with venetoclax treatment. Since venetoclax either alone or in combination with chemotherapy drugs are currently in clinical trials for other pediatric cancers, a phase 1b trial is imminent for treating DMGs with venetoclax in combination with radiation therapy.
Association of NR2F1, a tumor dormancy marker, with cancer cell proliferation and lymph node metastasis, and expression in cancer-associated fibroblasts in breast cancer.
Authors: Rongrong Wu, Masanori Oshi, Mariko Asaoka, Yoshihisa Tokumaru, Takashi Ishikawa, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2022)

e12550 Background: It is now well accepted that some cancer cells remain in quiescent state and survive through adjuvant systemic treatments, also known as tumor dormancy, which preserve the potential for late recurrence. NR2F1 is a known biomarker for dormant cancer cells, which suppress cell proliferation in experimental models. Here, we hypothesized that patient breast cancer (BC) with high NR2F1 gene expression is associated with less cell proliferation and worse survival. Methods: More than 7000 patients from 3 large-scale primary and 5 metastatic BC patient cohorts and 2 single-cell sequencing cohorts were analyzed. Results: NR2F1 expression was upregulated in dormant cell lines and in bone metastatic clone cells compared with mother 4T1 cells. High NR2F1 BC enriched multiple metastasis-related pathways such as TGFβ, EMT, angiogenesis, as well as cancer stem cell-related signaling (NOTCH, HEDGEHOG, and Wntβ-catenin). As expected, all 5 cell proliferation-related gene sets including E2F Targets and G2M Checkpoints were enriched in low NR2F1 BC, and so was MKI67 expression. Unexpectedly, there were no consistent association between NR2F1 expression and survival among the 3 cohorts. Three out of four cohorts demonstrated significantly high NR2F1 expression in primary BC with lymph node metastasis. There was no difference in NR2F1 expression in primary BC by the distant metastasis in the four cohorts, by the metastatic sites, or between the primary and metastatic BC neither. Given the discrepancy between the biology and clinical outcome of high NR2F1 BC, we performed the functional analysis exclusively . Surprisingly, there were no consistent enrichment of metastasis-related gene sets nor downregulation of cell proliferation-related gene sets to high NR2F1 expression cancer cells, unlike the analyses of bulk tumors. Intratumoral heterogeneity, HRD, proliferation score, and mutation load were all less in high NR2F1 BC, along with IFN-γ response and TIL fractions. Infiltration of immune cells such as Th1 and Th2 T-cells, M1 and M2 macrophages were all less, while stromal cells such as adipocytes, fibroblasts, stromal cells and endothelial cells were more abundant in high NR2F1 BC. Surprisingly, NR2F1 was barely expressed in cancer cells and was most highly expressed in cancer-associated fibroblasts consistently regardless of subtypes in two independent single-cell sequence cohorts. The expression of NR2F1 was higher in inflammatory than myofibroblastic CAFs, and that of CAFs, but not cancer cells, was associated with lymph node metastasis or advanced stage. Conclusions: The tumor dormancy marker NR2F1 expression in primary BC is associated with mechanism of metastasis and suppression of cancer growth, but is most expressed in cancer-associated fibroblasts in the tumor microenvironment.
The cost of living crisis is harming mental health, partly because of previous cuts to social security
Authors: Kate Andersen, Aaron Reeves
Journal: BMJ (2022)

The cost of living crisis is harming mental health, partly because of previous cuts to social security As the government announces measures to help the cost of living crisis, Kate Andersen and Aaron Reeves discuss the impact of financial insecurity on people's mental health Kate Andersen, 1 Aaron Reeves 2The surge in prices over recent months has created a cost of living crisis that is exacerbating insecurity and harming people's mental health.The Food Foundation warned recently that more than two million adults in the UK have gone without food for a day because of the rising cost of living.This is not inevitable.Yes, when prices rise faster than earnings, this puts additional financial and emotional strain on households.But in contexts where social security is more generous, this strain is minimised.Indeed, in some places, this strain has been entirely removed.
Sentinel lymph node biopsy in Merkel cell carcinoma: A multi-institutional study from the Pan-Canadian Merkel Cell Collaborative.
Authors: Megan E Delisle, Brittany Dingley, Sameer Apte, Ranjeeta Mallick, Trevor D Hamilton, Heather Stuart, Valerie Francescutti, Greg McKinnon, Evan Jost, Alexandra Easson, Shaila J. Merchant, Pamela Hebbard, Frances Catriona Wright, David Berger Richardson, Rami Younan, Ari Meguerditchian, Alex Mathieson, Jessika Hetu, Stephanie Johnson, Carolyn Nessim
Journal: Journal of Clinical Oncology (2022)

9583 Background: There is controversy regarding sentinel lymph node biopsy (SLNB) in clinically node-negative Merkel Cell Carcinoma (MCC). We compared MCC recurrence and survival between patients who did versus did not undergo a SLNB. Methods: Patients with MCC across 13 Canadian centers were reviewed, from 2000-2018. Of a total cohort of 750 patients, 485 had clinically node-negative disease at presentation. A propensity score was created. The association between SLNB and local, regional and distant recurrence, and cancer-specific and overall survival were evaluated using competing risks and Cox proportional hazards regression. Results: 195 patients (40.2%) underwent a SLNB. SLNB was performed more commonly in younger, healthier patients with MCC located in the extremities or torso (Table). The results of 177 SLNBs were available; 60 (33.9%) were positive. SLNB-positive patients underwent completion dissection (n=15, 25%), completion dissection and nodal radiation (n=22, 36.7%), nodal radiation alone (n=18, 30%) or observation (n=5, 8.3%). Patients who did not undergo a SLNB underwent nodal radiation alone (n=40, 13.8%) or observation (n=250, 86.2%). The median follow-up was 2.7 years (range 0.2-14.4). The regional recurrence rate was 14.5% (n=17) among SLNB-negative versus 15% (n=9) among SLNB-positive patients. Among patients who did not undergo a SLNB, the regional recurrence rate was 25.2% (n=63) among those who underwent observation and 15% (n=6) among those who received nodal radiation alone. After propensity score matching, SLNB patients had a lower risk of regional recurrence (sHR 0.54 95% CI 0.34-0.86 p=0.01) and improved overall survival (HR 0.32 95% CI 0.23-0.45 p&lt;0.01), but there was no difference in local recurrence (sHR 0.92 95% CI 0.50-1.69 p=0.79), distant recurrence (sHR 0.88 95% CI 0.52-1.49 p=0.63), or cancer-specific survival (HR 0.67 95% CI 0.31-1.45 p=0.31). Conclusions: SLNB is associated with a reduced risk of regional recurrence and improved overall survival. The role of SLNB in selecting patients for emerging therapies, such as immunotherapy, needs to be evaluated. [Table: see text]
Predictors of biomarker testing among patients (pts) with metastatic non–small cell lung cancer (mNSCLC).
Authors: Nicholas J. Robert, Liwei Chen, Janet L. Espirito, Mandar Karhade, Makenzi Colleen Evangelist, Marcus A. Neubauer, Susie A. Bullock, Jennifer M. Walberg, Robert L. Coleman
Journal: Journal of Clinical Oncology (2022)

9130 Background: The MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) Consortium pragmatic study assessed real-world biomarker testing rates for mNSCLC within The US Oncology Network of over 1,000 providers. We previously reported that 90% of pts had at least one test performed for ALK, BRAF, EGFR, ROS1, or PD-L1, but only 46% had testing for all 5. We examined patient factors associated with rates of biomarker testing. Methods: Retrospective observational chart review study of pts with mNSCLC initiating first-line systemic therapy between 04/01/2018 and 03/31/2020. Patient characteristics including age, sex, race, geographic location, BMI, laboratory values, histology, performance status, stage at diagnosis, and comorbidities were obtained from iKnowMed electronic health records. Predictors of biomarker testing were identified using multivariable logistic regression. Results: Of the 3474 adults included in the study, median age was 69 years (range 23-90), 51% female, 65% White, 8% Black or African American, and 46% treated in the South US census region. Histology was adenocarcinoma in 74% and squamous cell carcinoma in 19%. Modeling for any biomarker testing resulted in histology and geographic region as significantly associated with increased likelihood of testing: adenocarcinoma vs squamous cell, odds ratio (OR) 1.76 (CI 1.33-3.23, p&lt;0.0001) and Midwest vs South, OR 2.04 (CI 1.24-3.34, p=0.005). For comprehensive testing of all 5 biomarkers, increased albumin, adenocarcinoma or not otherwise specified histology, Midwest, Northeast or West geographic regions, and larger practice size were all significantly associated with increased likelihood of testing, while Black or African American race was associated with significantly decreased likelihood of testing (Table). Conclusions: Black or African American race, smaller practice size, Southern practice, and squamous cell histology were significantly associated with lower comprehensive biomarker testing rates. Understanding clinical and social determinants of health will be important when evaluating interventions to improve testing rates in the prospective phases of the MYLUNG study. [Table: see text]
Can CA 19-9 predict inferior surgical and pathological outcomes for resectable pancreatic cancer?
Authors: Iktej Singh Jabbal, Arun Nagarajan, Mayank Roy, Carlos Rivera, Marita Yaghi, Hong Liang, Timmy Q. Nguyen, Tiffany L. George, Zeina A. Nahleh, Conrad H Simpfendorfer
Journal: Journal of Clinical Oncology (2022)

e16228 Background: Previous data have established that patients with pancreatic surgical specimens showing lymphovascular invasion (LVI) and positive surgical resection margins are associated with poor survival outcomes. However, there are no biomarkers to identify these high-risk patients preoperatively. In this study, we hypothesized that increased carbohydrate antigen 19-9 (CA 19-9) levels could be used to predict high-risk resectable pancreatic cancer features, including LVI and positive residual margins, thereby guiding the surgical decision-making process. Methods: We sampled the National Cancer Database for patients undergoing pancreatic cancer resection between 2004-2018. Logistic regression analysis was performed to analyze sociodemographic and disease characteristics associated with elevated CA 19-9 levels (&gt; 98 U/ml) versus low CA 19-9 levels (&lt; 98 U/ml). Additionally, Cox regression analyses were used to compare hazard ratios for demographic and disease characteristics. A p &lt; 0.05 was considered statistically significant. Results: 12208 patients (50.76% males) with pancreatic cancer were sampled. Pathological findings of LVI (n = 5963), microscopic residual tumor margins (R1) (n = 1547), and residual margins (R), not otherwise specified (NOS) (n = 885) had a stronger association with high preoperative CA 19-9 levels when compared to those with low CA 19-9 levels (LVI: OR 1.212, 95% CI 1.125–1.305, p &lt; 0.001, R1: OR 1.260, 95% CI 1.129–1.408, p = 0.001 and R NOS: OR 1.212, 95% CI 1.052–1.395, p = 0.008). Macroscopic residual margins (R2) (n = 85) were also associated with high CA 19-9 but statistically not significant (OR 1.242, 95% CI 0.802–1.924, p = 0.332) probably due to the low sample size for this subpopulation. Furthermore, all the factors listed below were independently associated with poor prognosis: (A) Elevated CA 19-9 levels: HR 1.411, 95% CI 1.350–1.475, p &lt; 0.001, (B) LVI: HR 1.333, 95% CI 1.275–1.394, p &lt; 0.001, (C) R NOS: HR = 1.517, 95% CI = 1.401–1.643, p &lt; 0.001, (D) R1: HR 1.594, 95% CI 1.499–1.695, p &lt; 0.001, (E) R2: HR 2.015, 95% CI 1.597–2.543, p &lt; 0.001. Conclusions: Elevated CA 19-9 can be used as a biomarker to identify a subset of pancreatic cancer patients with high-risk surgical pathological features such as LVI or residual tumor margins. In these patients, perhaps neoadjuvant chemotherapy can facilitate downstaging and provide superior surgical and oncological outcomes.
Illness perception and concordance between prostate cancer survivors and caregivers and adherence to self-management behaviors.
Authors: Karisma Pantaleon, Courtney Chan, Ying Yuan, Jenny J. Lin
Journal: Journal of Clinical Oncology (2022)

e24002 Background: Illness beliefs are important determinants of self-management behaviors (SMBs). Spousal or informal caregiver involvement improves clinical outcomes in non-cancer survivors with chronic diseases. However, very little is known about the influence that caregivers have on comorbid disease SMBs in cancer survivors. In this study, we aim to understand and identify concordance in illness beliefs and perceptions between caregivers and prostate cancer survivors and to determine their impact on hypertension (HTN) SMBs. Methods: Survivors and their caregivers completed surveys assessing their beliefs and perceptions and SMBs regarding survivors’ HTN. Both survivors and caregivers answered the Brief Illness Perception Questionnaire (BIPQ) to assess beliefs and perceptions of survivors’ HTN. The BIPQ score is a sum of eight questions with a higher sum score indicating a more threatening view of the illness. Survivors reported adherence to SMBs using the Medication Adherence Report Scale (MARS) and Hypertension Self-Care Activity Level Effects (HSCALE). MARS scores &gt;4.5 were considered adherent. The HSCALE isdivided into five sub-scores – diet, physical activity, smoking behavior, weight management and alcohol intake and each was score was dichotomized. Cohen’s Kappa statistic assessed concordance between survivor and caregiver dyad responses to the BIPQ. Logistic regression assessed associations between survivor and caregiver BIPQ scores and odds of SMB adherence. Results: This analysis included 55 dyads. Mean age of survivors was 70.4 years ± 9.6; 12 (22%) were Black, 36 (65%) were White, 2 (4%) were Asian and 3 (5%) were other race. Mean age of caregivers was 64.4 years ± 10.5, 9 (16%) self-identified as Black, 35 (64%) White, 2 (4%) Asian and 3 (5%) other race. Survivors and caregivers had fair agreements about how much HTN affected survivors’ lives (k = 0.147, p = 0.008), how concerned survivors are about their HTN k = 0.130, p = 0.014), and HTN’s emotional impact on survivors (k = 0.185, p = 0.002). However, survivor-caregiver concordance about HTN had no significant impact on survivors’ SMBs. In contrast, caregivers’ beliefs about HTN was associated with survivors’ SMB such that a 1-point increase in caregiver’s BIPQ score was associated with 8% increase in the odds of survivors’ self-reported weight adherence (p = 0.0314). Survivors’ HTN beliefs were not associated with adherence to SMBs. Conclusions: Caregivers have a significant influence on prostate cancer survivors’ adherence to weight-related SMB, demonstrating that it is important to also educate caregivers who support cancer survivors with chronic comorbidities. Future analysis will include a larger cohort to better understand the interrelationship between caregivers’ illness beliefs and survivors’ SMBs and may help clinicians better direct interventions to improve survivorship outcomes.
Pathologic complete response (pCR) rates for HR+/HER2- breast cancer by molecular subtype in the I-SPY2 Trial.
Authors: Laura Ann Huppert, Hope S. Rugo, Lajos Pusztai, Rita A. Mukhtar, Amy Jo Chien, Christina Yau, Denise M. Wolf, Donald A. Berry, Laura van 't Veer, Douglas Yee, Angela DeMichele, Laura Esserman
Journal: Journal of Clinical Oncology (2022)

504 Background: Hormone receptor positive (HR+), HER2- breast cancer (BC) is a heterogenous disease. We hypothesized that molecular subtypes capturing luminal, basal, and immune biology could predict response for patients (pts) with HR+/HER2- disease in the I-SPY2 trial. Methods: I-SPY2 trial is a phase II, randomized, adaptive study evaluating multiple investigational agents as neoadjuvant BC therapy; the primary endpoint is estimated pCR rate. Investigational agents are given with control weekly paclitaxel x 12, followed by AC x 4. Regimens graduate when the predicted pCR rate in any signature meets the pre-specified threshold of 85% probability of success in a hypothetical 300 pt randomized, phase 3 trial. We analyzed estimated pCR rates for the 1st 7 investigational agents in the HR+/HER- subset, analyzed by clinical/molecular features: BluePrint (BP) Luminal vs. Basal, Mammaprint High1 [MP1] vs. Mammaprint High2 [MP2], MP2 is &lt; -0.57, Responsive Predictive Subtype-5 (RPS-5) (classification based on HR, HER2, immune, DNA-repair, and basal/luminal markers), histology, and stage/nodal status. Results: 38% (379/987) of pts had HR+/HER2- disease. Only pembrolizumab met the pre-specified graduation criteria for HR+/HER2- BC. pCR rates by treatment arm and molecular subtype are described in the Table. 28% were MP2; 72% were MP1. Overall, pCR rates were higher in pts with MP2 vs MP1 disease (30% vs 11%) including with pembrolizumab (55% vs. 21%). 29% were BP Basal, 71% were BP Luminal; BP Basal was more likely to be MP2 than BP Luminal (77% vs 8%). In all arms except MK2206, HR+/HER2- BP Basal pts were more likely to achieve pCR than BP Luminal pts. For MK2206, BP Luminal pts were more likely to achieve pCR. Immune+ by RPS-5 (39% of HR+/HER2-) predicted pCR to pembrolizumab irrespective of BP Basal or Luminal status (11 pCR/16 pts). Results by histology and stage/nodal status will also be reported. Conclusions: Our data suggest that MP2 and BP Basal signatures identify a subset of HR+/HER2- BC more likely to respond to neoadjuvant therapy; and that an immune signature can identify pts more likely to respond to pembrolizumab. These findings will aid in guiding prioritization of targeted agents with the goal to optimize pCR for all pts. Clinical trial information: NCT01042379. [Table: see text]
Patterns of Children’s Blood Lead Screening and Blood Lead Levels in North Carolina, 2011–2018—Who Is Tested, Who Is Missed?
Authors: Elizabeth M. Kamai, Julie L. Daniels, Paul L. Delamater, Bruce P. Lanphear, Jacqueline MacDonald Gibson, David B. Richardson
Journal: Environmental Health Perspectives (2022)

Background: No safe level of lead in blood has been identified. Blood lead testing is required for children on Medicaid, but it is at the discretion of providers and parents for others. Elevated blood lead levels (EBLLs) cannot be identified in children who are not tested. Objectives: The aims of this research were to identify determinants of lead testing and EBLLs among North Carolina children and estimate the number of additional children with EBLLs among those not tested. Methods: We linked geocoded North Carolina birth certificates from 2011–2016 to 2010 U.S. Census data and North Carolina blood lead test results from 2011–2018. We estimated the probability of being screened for lead and created inverse probability (IP) of testing weights. We evaluated the risk of an EBLL of ≥3μg/dL at &lt;30 months of age, conditional on characteristics at birth, using generalized linear models and then applied IP weights to account for missing blood lead results among unscreened children. We estimated the number of additional children with EBLLs of all North Carolina children using the IP-weighted population and bootstrapping to produce 95% credible intervals (CrI). Results: Mothers of the 63.5% of children (402,002 of 633,159) linked to a blood lead test result were disproportionately young, Hispanic, Black, American Indian, or on Medicaid. In full models, maternal age ≤20y [risk ratio (RR)=1.10; 95% confidence interval (CI): 1.13, 1.20] or smoking (RR=1.14; 95% CI: 1.12, 1.17); proximity to a major roadway (RR=1.10; 95% CI: 1.05, 1.15); proximity to a lead-releasing Toxics Release Inventory site (RR=1.08; 95% CI: 1.03, 1.14) or a National Emissions Inventory site (RR=1.11; 95% CI: 1.07, 1.14); and living in neighborhoods with more housing built before 1950 (RR=1.10; 95% CI: 1.05, 1.14) or before 1940 (RR=1.18; 95% CI: 1.11, 1.25) or more vacant housing (RR=1.14; 95% CI: 1.11, 1.17) were associated with an increased risk of EBLL, whereas overlap with a public water service system was associated with a decreased risk of EBLL (RR=0.85; 95% CI: 0.83, 0.87). Children of Black mothers were no more likely than children of White mothers to have EBLLs (RR=0.98; 95% CI: 0.96, 1.01). Complete blood lead screening in 2011–2018 may have identified an additional 17,543 (95% CrI: 17,462, 17,650) children with EBLLs ≥3μg/dL. Discussion: Our results indicate that current North Carolina lead screening strategies fail to identify over 30% (17,543 of 57,398) of children with subclinical lead poisoning and that accounting for characteristics at birth alters the conclusions about racial disparities in children’s EBLLs. https://doi.org/10.1289/EHP10335